Kumar M J Mahesh, Ponvijay K S, Nandhini R, Nagarajan R S, Jose J, Srinivas G, Nagarajan P, Venkatesan R, Kumar Kishor, Singh S
Centre For Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.
BMC Cancer. 2007 Sep 20;7:180. doi: 10.1186/1471-2407-7-180.
Generation of novel spontaneous ER positive mammary tumor animal model from heterozygous NIH nude mice.
Using brother-sister mating with pedigree expansion system, we derived a colony of heterozygous breeding females showing ER-Positive tumors around the age of 6 months. Complete blood picture, differential leukocyte count, and serum levels of Estrogen, Alanine amino transferase (SGPT), Aspartate amino transferase (SGOT), total protein and albumin were estimated. Aspiration biopsies and microbiology were carried out. Gross pathology of the tumors and their metastatic potential were assessed. The tumors were excised and further characterized using histopathology, cytology, electron microscopy (EM), molecular markers and Mouse mammary Tumor Virus - Long Terminal Repeats (MMTV LTR) specific RT-PCR.
The tumors originated from 2nd or 5th or both the mammary glands and were multi-nodulated with variable central necrosis accompanied with an accumulation of inflammatory exudate. Significant increases in estrogen, SGPT, SGOT and neutrophils levels were noticed. Histopathologically, invasive nodular masses of pleomorphic tubular neoplastic epithelial cells invaded fibro-vascular stroma, adjacent dermis and subcutaneous tissue. Metastatic spread through hematogenous and regional lymph nodes, into liver, lungs, spleen, heart and dermal lymphatics was observed. EM picture revealed no viral particles and MMTV-negativity was confirmed through MMTV LTR-specific RT-PCR. High expression of ER alpha, moderate to high expression of proliferating cell nuclear antigen (PCNA), moderate expression of vimentin and Cytokeratin 19 (K19) and low expression of p53 were observed in tumor sections, when compared with that of the normal mammary gland.
Since 75% of human breast cancer were classified ER-positive and as our model mimics (in most of the characteristics, such as histopathology, metastasis, high estrogen levels) the ER-positive luminal epithelial-like human breast cancer, this model will be an attractive tool to understand the biology of estrogen-dependant breast cancer in women. To our knowledge, this is the first report of a spontaneous mammary model displaying regional lymph node involvement with both hematogenous and lymphatic spread to liver, lung, heart, spleen and lymph nodes.
从杂合子 NIH 裸鼠培育新型自发性雌激素受体（ER）阳性乳腺肿瘤动物模型。
采用具有谱系扩展系统的兄妹交配方式，我们培育出一群杂合育种雌性小鼠，它们在 6 个月龄左右出现 ER 阳性肿瘤。检测全血细胞计数、白细胞分类计数以及雌激素、丙氨酸氨基转移酶（SGPT）、天冬氨酸氨基转移酶（SGOT）、总蛋白和白蛋白的血清水平。进行穿刺活检和微生物学检测。评估肿瘤的大体病理学特征及其转移潜能。切除肿瘤并使用组织病理学、细胞学、电子显微镜（EM）、分子标志物以及小鼠乳腺肿瘤病毒 - 长末端重复序列（MMTV LTR）特异性逆转录 - 聚合酶链反应（RT - PCR）进一步进行特征分析。
肿瘤起源于第二或第五乳腺或两者皆有，呈多结节状，伴有不同程度的中央坏死，并伴有炎性渗出物积聚。雌激素、SGPT、SGOT 和中性粒细胞水平显著升高。组织病理学上，多形性管状肿瘤上皮细胞的浸润性结节肿块侵犯纤维血管间质、邻近真皮和皮下组织。观察到通过血行和区域淋巴结发生转移，扩散至肝脏、肺、脾脏、心脏和真皮淋巴管。电子显微镜图像未显示病毒颗粒，通过 MMTV LTR 特异性 RT - PCR 证实为 MMTV 阴性。与正常乳腺相比，肿瘤切片中雌激素受体α（ERα）高表达、增殖细胞核抗原（PCNA）中度至高表达、波形蛋白和细胞角蛋白 19（K19）中度表达以及 p53 低表达。
由于 75%的人类乳腺癌被归类为 ER 阳性，且我们的模型（在大多数特征方面，如组织病理学、转移、高雌激素水平）模拟了 ER 阳性管腔上皮样人类乳腺癌，该模型将成为理解女性雌激素依赖性乳腺癌生物学特性的有吸引力的工具。据我们所知，这是首个显示区域淋巴结受累且伴有血行和淋巴转移至肝脏、肺、心脏、脾脏和淋巴结的自发性乳腺模型的报告。
